Valacyclovir is an L-valyl ester prodrug of acyclovir. Acyclovir, 6H-purin-6-one, 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl], is a synthetic purine nucleoside analog derived from guanine, having the following chemical structure formula shown in FIG. I. 
Acyclovir has been found to have high anti-viral activity and is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses. See Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 1193-1198 (9th ed. 1996). Acyclovir, as its sodium salt, is commercially available under the brand name Zovirax®. U.S. Pat. No. 4,199,574 discloses the treatment of viral infections with acyclovir.
Valacyclovir, L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, has the following chemical structure formula shown in FIG. II. 
The U.S. Food and Drug Administration has approved valacyclovir for the treatment of herpes zoster and genital herpes. Valacyclovir hydrochloride is commercially available under the brand name Valtrex®.
For oral administration, it is more advantageous to administer valacyclovir rather than acyclovir because acyclovir is poorly absorbed from the gastrointestinal tract in both animals and humans. In contrast, valacyclovir is rapidly absorbed from the gastrointestinal tract after oral administration. Moreover, valacyclovir is converted rapidly to acyclovir after oral administration in healthy adults. The conversion of valacyclovir is thought to result from first-pass intestinal and hepatic metabolism through enzymatic hydrolysis.
U.S. Pat. No. 4,957,924 discloses amino acid esters of the purine nucleoside analog acyclovir, pharmaceutically acceptable salts thereof, and processes for the preparation of such compounds. Also disclosed are pharmaceutical formulations and the use of the disclosed compounds in the treatment of herpes virus infections. Valacyclovir and its salts, including the hydrochloride salt, are among the disclosed compounds.
In particular, the '924 patent discloses a method for preparing valacyclovir by condensation of a protected valine, wherein CBZ-valine, a catalytic amount of 4-dimethylaminopyridine, and dicyclohexylcarbodiimide, a coupling reagent, were added to a solution of acyclovir in dimethylformamide. The CBZ group was removed by catalytic hydrogenation, which requires using hydrogen gas and specialized equipment (e.g. an autoclave). This process also requires the removal of a resulting urea by-product that is formed from the dicyclohexylcarbodiimide coupling agent. Due to the challenges involved in the process of the '924 patent, there is clearly a need for a process for making valacyclovir that employs less severe deprotecting procedures and involves easier removal of by-products.